Phenolic carbamate esters are useful for various purposes, for instance as pharmaceuticals, e.g. antitumor agents, as biocides e.g. pesticides, and as intermediates for preparing such useful compounds. For example, phenolic N-bis(2-chloroethyl) carbamates, especially those deriving from phenols with estrogenic activity, are useful as antitumor agents or as intermediates for preparing such useful compounds (see e.g. Brit. Pat. 1.016.959 and Zimel, Neoplasma 12(1965):3, 297).
The best methods known and used for the preparation of phenolic N-disubstituted carbamates are the following:
(1) Reaction of a N-disubstituted carbamoyl chloride with a phenol. PA0 (2) Reaction of a phenol chloroformate with a secondary amine. These reactions are normally performed in pyridine or in an inert organic solvent in the presence of a suitable amine as a hydrogen chloride acceptor. PA0 K.sup.+ -18-crown-6 (1,4,7,10,13,16-hexaoxacyclooctadecane, PA0 K.sup.+ -dibenzo-18-crown-6 (2,3,11,12-dibenzo-1,4,7,10,13,16-hexaoxacyclooctadeca-2,11-diene), PA0 K.sup.+ -dicyclohexyl-18-crown-6, PA0 K.sup.+ -dibenzo-24-crown-8 (2,3,14,15-dibenzo-1,4,7,10,13,16,19,22-octaoxacyclotetracosa-2,14-diene), PA0 Na.sup.+ -15-crown-5 (1,4,7,10,13-pentaoxacyclopentadecane), PA0 Na.sup.+ -dibenzo-15-crown-5 (2,3,8,9-dibenzo-1,4,7,10,13-pentaoxacyclopentadeca-2,8-diene), PA0 Na.sup.+ -cyclohexyl-15-crown-5, PA0 Na.sup.+ -benzo-15-crown-5 (2,3-benzo-1,4,7,10,13-pentaoxacyclopentadecene-2), PA0 K.sup.+ -kryptofix.sup.R 222 (4,7,13,16,21,24-hexaoxo-1,10-diazabicyclo-/8.8.8/-hexacosane), PA0 Na.sup.+ -Kryptofix.sup.R 221 (4,7,13,16,21-pentaoxa-1,10-diazabicyclo-/8.8.5/-tricosane/, PA0 Li.sup.+ -Kryptofix.sup.R 211 (4,7,13,18-tetraoxa-1,10-diazabicyclo-/8.5.5/-tricosane). PA0 estra-1,3,5(10)-trien-3-ol-17-one(estrone) PA0 estra-1,3,5(10)-trien-3,17.beta.-diol(estradiol-17.beta.) PA0 estra-1,3,5(10)-trien-3,17.alpha.-diol(estradiol-17.alpha.) PA0 estra-1,3,5(10)-trien-3,16.alpha.,17.beta.-triol(estriol) PA0 estra-1,3,5(10)-trien-3,16.beta.,17.beta.-triol(16-epiestriol) PA0 estra-1,3,5(10)-trien-3,16.alpha.,17.alpha.-triol(17-epiestriol) PA0 estra-1,3,5(10)-trien-3,16.alpha.-diol-17-one PA0 estra-1,3,5(10)-trien-3,17.beta.-diol-16-one(16-ketoestradiol) PA0 17.alpha.-ethynylestra-1,3,5(10)-trien-3,17.beta.-diol(17.beta.-ethynylestr adiol) and ethers and esters of any of the foregoing, many of which are known. PA0 3,4-bis/4-hydroxyphenyl/-hexene-3 (diethylstilbestrol) PA0 3,4-bis/4-hydroxyphenyl/-hexa-2,4-diene (dienestrol) PA0 3,4-bis/4-hydroxyphenyl/-hexane (hexestrol).
The existing methods are unsatisfactory for several reasons. Firstly, the use of pyridine or other amines in the reaction necessitates recovery steps in the process and/or gives environmental and pollution problems. Secondly, method 1 is not generally applicable and fails for some carbamoyl chlorides. Thirdly, method 2 is not directly applicable in many cases without recourse to protective groups when the phenol contains groups which might react in the preparation of the chloroformate (for instance alcoholic hydroxyl groups).
It is an object of this invention, therefore, to provide an improved carbamoylation process for the preparation of phenolic N-disubstituted carbamates. It is also an object of this invention to provide an improved carbamoylation process for the manufacture of phenolic N-disubstituted carbamates, suitable for industrial practices and from which satisfactory yields and purity of the desired product can be obtained. Another object of the invention is to provide novel compounds and novel solutions, suitable as intermediates in said process. Further objects of the invention will become apparent hereinafter and still others will be apparent to one skilled in the art to which this invention pertains.
A known method for the catalysis of certain organic reactions is the so called "phase transfer catalysis" or "ion pair extraction". For reviews on this method see for instance J. Dockx - Synthesis 1973:8, 441 and E. V. Dehmlow - Angew. Chem. 86(1974):5, 187.
In such method the reaction of an organic compound (optionally dissolved in an organic solvent) with an ionized organic or inorganic compound is catalyzed by the presence of a phase transfer catalyst, i.e. a quaternary ammonium compound, or a Crown-ether (a macrocyclic polyether with metal complexing properties). The function of the catalyst is to make the ionized compound, which normally is insoluble in organic solvents, soluble as an ion pair with the quaternary ammonium ion (or the Crown-ether complex with an alkali metal cation) in the organic phase, thus promoting the desired reaction with the organic compound. Normally, the reaction is performed in a two-phase solvent system consisting of water and a halogenated hydrocarbon solvent.
The method as known is mainly used for the alkylation of inorganic anions or anions from acidic compounds. The method is neither known nor supposed to work for acylation, including carbamoylation, of organic compounds, in as much as water or aqueous alkali is of necessity present in the method. Hydrolysis is therefore an expected side reaction in the method and acylating agents are sensitive to hydrolysis. Acyl chlorides are in fact notorious for their hygroscopicity and instability even under normal conditions of humidity, so that they are always stored only in tightly sealed containers.
Despite such contrary indications it has now been found that it is possible to perform carbamoylation of phenols using N-disubstituted carbamoyl chlorides, i.e. tertiary carbamoyl chlorides, in a phase transfer catalyzed reaction in the presence of aqueous alkali metal hydroxide and a phase transfer catalyst to form N-disubstituted phenolic carbamate esters. It has also been found that, by using at least one equivalent of catalyst (based on the phenolic compound), it is also possible to perform this reaction in two steps, the first step being a reaction of the phenolic compound, aqueous alkali metal hydroxide, phase transfer catalyst and water-immiscible solvent, followed by separation of the obtained organic phase containing the ion pair, and the second step being a reaction of the ion pair with an N-disubstituted carbamoyl chloride in the organic phase to form the desired ester. The organic phase containing the ion pair may be used as such in the second step, or the ion pair may be isolated and thereafter used in the second step. When the ion pair is isolated, other solvents may be used in the second step than those employed in the first step, if so desired.
The single-step procedure is generally preferred, but the two-step procedure is frequently advantageous in cases where the particular acyl chloride employed is characterized by the highest order of instability. Although in the case of the two-step process the organic solvent containing the ion-pair (which is contacted with the acyl chloride) is separated from the aqueous phase, the solution is completely saturated with water.
Procedure of the present invention remarkably and unpredictably proceeds directly to the desired carbamate esters in high yields and purity, without substantial hydrolysis or other deterioration of the unstable acid chlorides.